Sirt2 Inhibition Enhances Metabolic Fitness and Effector Functions of Tumor-Reactive T Cells

Hamaidi, Imène; Zhang, Lin; Kim, Nayoung; Wang, Min-Hsuan; Iclozan, Cristina; Fang, Bin; Liu, Min; Koomen, John M.; Berglund, Anders; Yoder, Sean; Yao, Jiqiang; Engelman, Robert W.; Creelan, Ben; Conejo-Garcia, José R.; Antonia, Scott; Mulé, James J.; Kim, Sungjune

doi:10.1016/j.cmet.2020.07.008

Cited by 78 publications

(63 citation statements)

References 49 publications

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“…Similarly, the genetic/epigenetic mechanism for muted inflammatory response in EtOH with sepsis needs to be investigated. Lastly, evidence suggests that SIRT2 is a major metabolic regulator in cancer cells (Al‐Azzam, 2020; Hamaidi et al, 2020). The role of SIRT2 in metabolic perturbations in leukocytes and/or endothelial cells in EtOH with sepsis needs to be evaluated.…”

Section: Discussionmentioning

confidence: 99%

Ethanol Exposure Attenuates Immune Response in Sepsis via Sirtuin 2 Expression

Gandhirajan

Roychowdhury

Kibler

et al. 2021

Alcoholism Clin & Exp Res

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Background Sepsis and septic shock kill over 270,000 patients per year in the United States. Sepsis transitions from a hyper‐inflammatory to a hypo‐inflammatory phase. Alcohol dependence is a risk factor for mortality from sepsis. Ethanol (EtOH) exposure impairs pathogen clearance through mechanisms that are not fully understood. Sirtuin 2 (SIRT2) interferes with pathogen clearance in immune cells but its role in the effects of EtOH on sepsis is unknown. We studied the effect of EtOH exposure on hyper‐ and hypo‐inflammation and the role of SIRT2 in mice. Methods We exposed C57Bl/6 (WT) mice to EtOH via drinking water and used intraperitoneal cecal slurry (CS)‐induced sepsis to study: (i) 7‐day survival, (ii) leukocyte adhesion (LA) in the mesenteric microcirculation during hyper‐ and hypo‐inflammation, (iii) peritoneal cavity bacterial clearance, and (iv) SIRT2 expression in peritoneal macrophages. Using EtOH‐exposed and lipopolysaccharide (LPS)‐stimulated RAW 264.7 (RAW) cell macrophages for 4 hours or 24 hours, we studied: (i) tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), interleukin‐10 (IL‐10), and SIRT2 expression, and (ii) the effect of the SIRT2 inhibitor AK‐7 on inflammatory response at 24 hours. Lastly, we studied the effect of EtOH on sepsis in whole body Sirt2 knockout (SIRT2KO) mice during hyper‐ and hypo‐inflammation, bacterial clearance, and 7‐day survival. Results WT EtOH‐sepsis mice showed: (i) Decreased survival, (ii) Muted LA in the microcirculation, (iii) Lower plasma TNF‐α and IL‐6 expression, (iv) Decreased bacterial clearance, and (v) Increased SIRT2 expression in peritoneal macrophages versus vehicle‐sepsis. EtOH‐exposed LPS‐stimulated RAW cells showed: (i) Muted TNF‐α, IL‐6, and increased IL‐10 expression at 4 hours, (ii) endotoxin tolerance at 24 hours, and (iii) reversal of endotoxin tolerance with the SIRT2 inhibitor AK‐7. EtOH‐exposed SIRT2KO‐sepsis mice showed greater 7‐day survival, LA, and bacterial clearance than WT EtOH‐sepsis mice. Conclusion EtOH exposure decreases survival and reduces the inflammatory response to sepsis via increased SIRT2 expression. SIRT2 is a potential therapeutic target in EtOH with sepsis.

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Section: Discussionmentioning

confidence: 99%

Ethanol Exposure Attenuates Immune Response in Sepsis via Sirtuin 2 Expression

Gandhirajan

Roychowdhury

Kibler

et al. 2021

Alcoholism Clin & Exp Res

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“…Moreover, another study identified the negative correlation between response to tumor-infiltrating lymphocyte (TIL) therapy and upregulation of Sirt2 in human TILs. This study indicated that Sirt2-deficient T-cells increased antitumor activity resulting from upregulated oxidative phosphorylation and glycolysis, following the enhancement of effector functions and proliferation [83]. A remarkable finding regarding immunotherapy indicated that tryptophan metabolites related to the kynurenine pathway and IDO-1 activity were potential targets of novel immunotherapy.…”

Section: Target Discoverymentioning

confidence: 80%

The Comprehensive “Omics” Approach from Metabolomics to Advanced Omics for Development of Immune Checkpoint Inhibitors: Potential Strategies for Next Generation of Cancer Immunotherapy

Yoon

Lee

Chae

et al. 2021

IJMS

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In the past decade, immunotherapies have been emerging as an effective way to treat cancer. Among several categories of immunotherapies, immune checkpoint inhibitors (ICIs) are the most well-known and widely used options for cancer treatment. Although several studies continue, this treatment option has yet to be developed into a precise application in the clinical setting. Recently, omics as a high-throughput technique for understanding the genome, transcriptome, proteome, and metabolome has revolutionized medical research and led to integrative interpretation to advance our understanding of biological systems. Advanced omics techniques, such as multi-omics, single-cell omics, and typical omics approaches, have been adopted to investigate various cancer immunotherapies. In this review, we highlight metabolomic studies regarding the development of ICIs involved in the discovery of targets or mechanisms of action and assessment of clinical outcomes, including drug response and resistance and propose biomarkers. Furthermore, we also discuss the genomics, proteomics, and advanced omics studies providing insights and comprehensive or novel approaches for ICI development. The overview of ICI studies suggests potential strategies for the development of other cancer immunotherapies using omics techniques in future studies.

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“…In addition, SoNar-low cells had much higher level of both fatty acyl carnitines and fatty acid oxidation than that of SoNar-high cells, indicating that SoNar-low cells may also use fatty acid as an alternative resource of energy that depends on the TCA pathway (fig. S2, F and G) (32). It also seemed that glucose metabolism had the major contribution to the increase in oxidative phosphorylation level in SoNar-low cells as compared to the fatty acid or glutamine metabolism ( fig.…”

Section: Sonar-low B-all Cells Prefer Using Oxidative Phosphorylationmentioning

confidence: 89%

Oxidative phosphorylation enhances the leukemogenic capacity and resistance to chemotherapy of B cell acute lymphoblastic leukemia

et al. 2021

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How metabolic status controls the fates of different types of leukemia cells remains elusive. Using a SoNar-transgenic mouse line, we demonstrated that B cell acute lymphoblastic leukemia (B-ALL) cells had a preference in using oxidative phosphorylation. B-ALL cells with a low SoNar ratio (SoNar-low) had enhanced mitochondrial respiration capacity, mainly resided in the vascular niche, and were enriched with more functional leukemia-initiating cells than that of SoNar-high cells in a murine B-ALL model. The SoNar-low cells were more resistant to cytosine arabinoside (Ara-C) treatment. cyclic adenosine 3′,5′-monophosphate response element–binding protein transactivated pyruvate dehydrogenase complex component X and cytidine deaminase to maintain the oxidative phosphorylation level and Ara-C–induced resistance. SoNar-low human primary B-ALL cells also had a preference for oxidative phosphorylation. Suppressing oxidative phosphorylation with several drugs sufficiently attenuated Ara-C–induced resistance. Our study provides a unique angle for understanding the potential connections between metabolism and B-ALL cell fates.

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Sirt2 Inhibition Enhances Metabolic Fitness and Effector Functions of Tumor-Reactive T Cells

Cited by 78 publications

References 49 publications

Ethanol Exposure Attenuates Immune Response in Sepsis via Sirtuin 2 Expression

Ethanol Exposure Attenuates Immune Response in Sepsis via Sirtuin 2 Expression

The Comprehensive “Omics” Approach from Metabolomics to Advanced Omics for Development of Immune Checkpoint Inhibitors: Potential Strategies for Next Generation of Cancer Immunotherapy

Oxidative phosphorylation enhances the leukemogenic capacity and resistance to chemotherapy of B cell acute lymphoblastic leukemia

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